1. Field of the Use
The present invention relates to a method of encapsulating anthracycline glycosides in liposomes and liposomal compositions obtainable thereby.
2. Description of the Background
Anthracycline glycosides are compounds which are known to exhibit both antibiotic and anticancer activity. Generally, anthracycline glycosides contain an amino-sugar linked to a tetrahydronaphthacene chromophore by a glycoside bond. Among this group of compounds are doxorubicin (adriamycin, a product of U.S. Pat. No. 3,590,028) and daunorubicin (U.S. Pat. No. 4,012,284) as well as analogs described in U.S. Pat. No. 3,686,136 and Yamamoto, K. et al., J. Med. Chem. 15, 872 (1973); German patent nos. 2,327,211; 2,557,537; and 1,920,198; Bachman, E. et al., Agents and Actions, 5/4, 383, 1975); Chandra, P., Cancer Chemotherapy, Rep. 6,115 (1975); Arcamone, F. et al., id. at 123; and Zbinden, G. et al., Cancer Chemotherapy, Rep. 4, 707 (1975).
Doxorubicin is one of the most commonly used antineoplastic agents and has demonstrated activity for a wide range of human cancers such as leukemia, lymphoma and solid tumors. The mechanisms of action of anthracycline glycosides are considered to involve the blocking of the functions of deoxyribonucleic acid (DNA) by intercalation in the DNA structure. Unfortunately, clinical use of these compounds is severely hampered by dose-limiting cardiotoxic effects. The cardiotoxicity of both doxorubicin and daunorubicin has been well documented. Further, the cardiotoxic effect has been shown to be cumulative and may lead to congestive heart failure. This cardiotoxicity is quite specific and pharmacologic distribution studies have shown a selective tropism to the heart muscle.
Attempts to prevent anthracycline glycoside cardiotoxicity have included reliance on combination chemotherapy to produce additive or synergistic effects so that the cumulative dosage of the anthracycline glycosides can be reduced, and concomitant administration of antioxidants to protect against cardiotoxic effects.
More recently, liposome delivery systems have been used to reduce anthracycline uptake in cardiac tissue, while preserving drug activity. See for example, U.S. Pat. No. 4,419,348. In using this methodology, it is found that doxorubicin in cardiolipin containing liposome exerts antitumor activity at doses that cause fewer myocardial alterations than the same dose of free doxorubicin. For example, prevention of doxorubicin cardiotoxicity in beagles by liposomal encapsulation has also been shown. Generally, the preparation of this form of doxorubicin involves a two-step preparation process, which entails complexing of the drug with cardiolipin and subsequently encapsulating the complex in liposomes. However, this preparation is very difficult to manage at an industrial level, particularly in conserving good encapsulation efficiency and preserving anthracycline glycoside stability.
Hence, a need exists for a method of preparing liposomal doxorubicin compositions which conserves good encapsulation efficiency while preserving anthracycline glycoside stability.